scholarly journals Exploring Better Strategies for RAS Mutation-Associated EGFR-Targeted Resistance in Colorectal Cancer: From the Perspective of Cancer Community Ecology

2021 ◽  
Vol 11 ◽  
Author(s):  
Xiaojie Wang ◽  
Wenchuan Wu ◽  
Zhifang Zheng ◽  
Pan Chi
Keyword(s):  
Colorectal Cancer ◽  
Community Ecology ◽  
Cancer Progression ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Evolutionary Process ◽  
Continuous Treatment ◽  
Exclusion Principle ◽  
Competitive Release

RAS is the most common mutated gene in colorectal cancer (CRC), and its occurrence is associated with primary and acquired resistance to anti-epidermal growth factor receptor (EGFR) blockade. Cancer community ecology, such as the competitive exclusion principle, is a valuable focus and would contribute to the understanding of drug resistance. We have presented several articles on RAS mutant clonal evolution monitoring during anti-EGFR treatment in CRC. In these articles, the availability of serially collected samples provided a unique opportunity to model the tumor evolutionary process from the perspective of cancer community ecology in those patients upon treatment. In this perspective article, we presented a theoretical basis and evidence from several experimental or phase II clinical trials for the contemporary application of ecological mechanisms in CRC treatment. In general, a reduction in targetable RAS wild-type cells to a maximum tolerated extent, such as continuous treatment, might lead to the competitive release of inextirpable RAS mutant cells and cancer progression. A full understanding of subclonal competition might be beneficial in managing CRC. Several ecological strategies, including anti-EGFR treatment reintroduced at an appropriate point of time for RAS mutant patients, intermittent treatment instead of continuous treatment, the appropriate sequence of nonselective targeted therapy, and combination therapy, were proposed.

The occurrence of mutant KRAS clones in the blood of RAS wild type colorectal cancer patients: Impact of response or failure under anti-EGFR therapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 600-600
Author(s):  
Andreas W. Berger ◽  
Daniel Schwerdel ◽  
Hanna Welz ◽  
Thomas Jens Ettrich ◽  
Peter Moeller ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clonal Selection ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Dynamic Monitoring ◽  
Tumor Evolution ◽  
Genetic Profile ◽  
Wild Type ◽  
Initial State ◽  
Kras Mutations

600 Background: Colorectal cancer (CRC) is characterized by a high level of genetic heterogeneity. In addition, changes in the genetic profile induced by chemotherapy affect treatment results. Acquired resistance of tumors is defined as a result of clonal evolution and clonal selection under systemic chemotherapy. Repeated tumor tissue biopsies are difficult to obtain and cannot be easily used for dynamic monitoring of therapy response or failure due to marked tumor heterogeneity. Promising data for circulating cell-free tumor DNA (ctDNA) as a tool for studying tumor evolution were recently published. Methods: In this study we analyzed ctDNA from patients with metastatic CRC during treatment with anti-epidermal growth factor receptor (EGFR) antibodies (cetuximab/panitumumab). By droplet digital PCR we performed genotyping of CRC tissue and tracking of clonal evolution of the most frequent KRAS mutations (G12A, G12C, G12D, G12R, G12S, G12V, G13C, G13D, Q61R, A146T and A59T) in plasma ctDNA. Results: In initial KRAS wild type tumors several mutated KRAS clones occurred in plasma under the course of anti-EGFR-therapy indicating an increasing acquired resistance to the given therapy leading to a disease progression. Some of these mutations declined upon discontinuation of anti-EGFR therapy. Conclusions: Based on these results we hypothesize that the initial state of KRAS wild type situation seems to be restored in some cases. This opens up the possibility to reinduce anti-EGFR therapy in later therapy lines.

KLF4 p.A472D mutation: An acquired resistant mutation to cetuximab in colorectal cancer.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. e15077-e15077
Author(s):  
Liu Yang ◽  
Jiahong Jiang ◽  
Lianpeng Chang ◽  
Yaping Xu ◽  
Chao Ni ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Function Analysis ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Circulating Tumor Dna ◽  
Resistance Mechanisms ◽  
Sequencing Analysis ◽  
Kras Mutations ◽  
Target Capture ◽  
Epidermal Growth

e15077 Background: With the increase of treatment course, acquired resistance of epidermal growth factor receptor (EGFR) blockade is inevitable in patients with metastatic colorectal cancer (mCRC). KRAS mutations have been considered to be primary drivers of this acquired resistance; however, the potential function of other genes has not been extensively investigated. Methods: This study included 17 mCRC patients with acquired cetuximab resistance, and mutations in circulating tumor DNA (ctDNA) from plasma samples were identified using target-capture deep sequencing. Analysis of mutational prevalence in ctDNA, three CRC tissue-based datasets and one ctDNA dataset was performed. Mutation predicted with significant effect on acquired resistance was selected and the functional analysis was validated in CRC cells. Results: The prevalence of mutations identified in ctDNA was consistent with CRC tissue-based and ctDNA datasets. Clonal analysis revealed that 41.2% of patients were positive for at least one subclonal. Multiply resistance mechanisms of cetuximab were co-existed in individual patient, with one of them even harbored nine distinct mutations. In particularly, function analysis of Krüppel-like factor 4 (KLF4) mutation p.A472D revealed increased cetuximab resistance in CRC cells, which was associated with the increased phosphorylation of downstream EGFR signaling proteins. Conclusions: The KLF4 mutation p.A472D contributes to acquired cetuximab resistance in patients with mCRC and it may serve as a new biomarker useful in clinical application. Monitoring somatic mutations related to acquired cetuximab resistance in mCRC patients through ctDNA is an appropriate means of providing real-time insights useful for clinical reference and treatment planning.

scholarly journals Immune Resistance and EGFR Antagonists in Colorectal Cancer

Cancers ◽  
2019 ◽  
Vol 11 (8) ◽  
pp. 1089 ◽  
Author(s):  
Giordano ◽  
Remo ◽  
Porras ◽  
Pancione
Keyword(s):  
Colorectal Cancer ◽  
Tumor Microenvironment ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Therapy Resistance ◽  
Cell Interaction ◽  
Molecular Alterations ◽  
Immune Resistance ◽  
Epidermal Growth ◽  
Mechanistic Basis

: Targeting the epidermal growth factor receptor (EGFR) either alone or in combination with chemotherapy in patients with RAS wild type metastatic colorectal cancer (mCRC) has revolutionized the treatment of CRC, but with less results than initially envisaged. In recent years, the discovery of multiple pathways leading to the escape from anti-EGFR therapy has revealed an enormous complexity and heterogeneity of human CRC due to the intrinsic genomic instability and immune/cancer cell interaction. Therefore, understanding the mechanistic basis of acquired resistance to targeted therapies represents a major challenge to improve the clinical outcomes of patients with CRC. The latest findings strongly suggest that complex molecular alterations coupled with changes of the immune tumor microenvironment may substantially contribute to the clinical efficacy of EGFR antagonist. In this review, we discuss the most recent findings that contribute to both primary and acquired anti-EGFR therapy resistance. In addition, we analyze how strategies aiming to enhance the favorable effects in the tumor microenvironment may contribute to overcome resistance to EGFR therapies.

scholarly journals Prior acquired resistance to paclitaxel relays diverse EGFR-targeted therapy persistence mechanisms

2020 ◽  
Vol 6 (6) ◽  
pp. eaav7416 ◽  
Author(s):  
Mark Borris D. Aldonza ◽  
Jayoung Ku ◽  
Ji-Young Hong ◽  
Donghwa Kim ◽  
Seung Jung Yu ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Kinase Inhibitors ◽  
Clonal Evolution ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Cancer Recurrence ◽  
Resistant Cell ◽  
Small Scale ◽  
Primary Resistance ◽  
Egfr Tkis

Secondary drug resistance stems from dynamic clonal evolution during the development of a prior primary resistance. This collateral type of resistance is often a characteristic of cancer recurrence. Yet, mechanisms that drive this collateral resistance and their drug-specific trajectories are still poorly understood. Using resistance selection and small-scale pharmacological screens, we find that cancer cells with primary acquired resistance to the microtubule-stabilizing drug paclitaxel often develop tolerance to epidermal growth factor receptor–tyrosine kinase inhibitors (EGFR-TKIs), leading to formation of more stable resistant cell populations. We show that paclitaxel-resistant cancer cells follow distinct selection paths under EGFR-TKIs by enriching the stemness program, developing a highly glycolytic adaptive stress response, and rewiring an apoptosis control pathway. Collectively, our work demonstrates the alterations in cellular state stemming from paclitaxel failure that result in collateral resistance to EGFR-TKIs and points to new exploitable vulnerabilities during resistance evolution in the second-line treatment setting.

scholarly journals Fibroblast Growth Factor Receptor 2: Expression, Roles, and Potential As a Novel Molecular Target for Colorectal Cancer

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Yoko Matsuda ◽  
Junji Ueda ◽  
Toshiyuki Ishiwata
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cancer Progression ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Fibroblast Growth ◽  
Type Iv ◽  
Well Differentiated ◽  
Novel Target

The fibroblast growth factor receptor (FGFR) family consists of four members, named FGFR1, 2, 3, and 4. All 4 FGFRs and their ligands, fibroblast growth factors (FGFs), are expressed in colorectal cancer (CRC). Recent studies have shown that FGFR2 plays important roles in cancer progression; therefore, it is of great interest as a novel target for cancers. Expression of FGFR2 regulates migration, invasion, and growth in CRC. Expression of the FGFR2 isoform FGFR2 IIIb was associated with well-differentiated histological types, and its specific ligand, FGF7, enhanced angiogenesis and adhesion to type-IV collagen via FGFR2 IIIb in CRC. FGFR2 IIIc is detected in CRC, but its roles have not been well elucidated. Interactions between FGFR2 IIIb and IIIc and FGFs may play important roles in CRC via autocrine and/or paracrine signaling. Several kinds of molecular-targeting agents against FGFR2 have been developed; however, it is not clear how a cancer treatment can most effectively inhibit FGFR2 IIIb or FGFR2 IIIc, or both isoforms. The aim of this paper is to summarize the roles of FGFR2 and its isoforms in CRC and clarify whether they are potent therapeutic targets for CRC.

scholarly journals Signaling pathways involved in colorectal cancer progression

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Zahra Koveitypour ◽  
Farnoush Panahi ◽  
Mehrdad Vakilian ◽  
Maryam Peymani ◽  
Farzad Seyed Forootan ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Signaling Pathways ◽  
Cancer Progression ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Growth Factor Receptor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mapk Cascades

AbstractColorectal cancer (CRC) is the fourth leading cause of the worldwide cancer mortality. Different molecular mechanisms have been attributed to the development and progress of CRC. In this review, we will focus on the mitogen-activated protein kinase (MAPK) cascades downstream of the epidermal growth factor receptor (EGFR), Notch, PI3K/AKT pathway, transforming growth factor-β (TGF-β), and Wnt signaling pathways. Various mutations in the components of these signaling pathways have been linked to the development of CRC. Accordingly, numerous efforts have been carried out to target the signaling pathways to develop novel therapeutic approaches. Herein, we review the signaling pathways involved in the incidence and progression of CRC, and the strategies for the therapy targeting components of signaling pathways in CRC.

scholarly journals ADAM17 is required for EGF-R–induced intestinal tumors via IL-6 trans-signaling

2018 ◽  
Vol 215 (4) ◽  
pp. 1205-1225 ◽  
Author(s):  
Stefanie Schmidt ◽  
Neele Schumacher ◽  
Jeanette Schwarz ◽  
Simone Tangermann ◽  
Lukas Kenner ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Tumor Formation ◽  
Intestinal Cancer ◽  
Low Grade ◽  
Sequencing Analysis ◽  
Intestinal Epithelial ◽  
Therapeutic Success ◽  
Novel Strategy

Colorectal cancer is treated with antibodies blocking epidermal growth factor receptor (EGF-R), but therapeutic success is limited. EGF-R is stimulated by soluble ligands, which are derived from transmembrane precursors by ADAM17-mediated proteolytic cleavage. In mouse intestinal cancer models in the absence of ADAM17, tumorigenesis was almost completely inhibited, and the few remaining tumors were of low-grade dysplasia. RNA sequencing analysis demonstrated down-regulation of STAT3 and Wnt pathway components. Because EGF-R on myeloid cells, but not on intestinal epithelial cells, is required for intestinal cancer and because IL-6 is induced via EGF-R stimulation, we analyzed the role of IL-6 signaling. Tumor formation was equally impaired in IL-6−/− mice and sgp130Fc transgenic mice, in which only trans-signaling via soluble IL-6R is abrogated. ADAM17 is needed for EGF-R–mediated induction of IL-6 synthesis, which via IL-6 trans-signaling induces β-catenin–dependent tumorigenesis. Our data reveal the possibility of a novel strategy for treatment of colorectal cancer that could circumvent intrinsic and acquired resistance to EGF-R blockade.

scholarly journals Pro-Oncogenic c-Met/EGFR, Biomarker Signatures of the Tumor Microenvironment are Clinical and Therapy Response Prognosticators in Colorectal Cancer, and Therapeutic Targets of 3-Phenyl-2H-benzo[e][1,3]-Oxazine-2,4(3H)-Dione Derivatives

2021 ◽  
Vol 12 ◽  
Author(s):  
Bashir Lawal ◽  
Yu-Chi Wang ◽  
Alexander T. H. Wu ◽  
Hsu-Shan Huang
Keyword(s):  
Colorectal Cancer ◽  
Growth Factor ◽  
Cancer Progression ◽  
Wide Spectrum ◽  
Growth Factor Receptor ◽  
Genetic Alterations ◽  
Anticancer Activities ◽  
Mtor Inhibition

Genetic and environmental factors play important roles in cancer progression, metastasis, and drug resistance. Herein, we used a multiomics data analysis to evaluate the predictive and prognostic roles of genetic and epigenetic modulation of c-MET (hepatocyte growth factor receptor)/epidermal growth factor receptor (EGFR) in colorectal cancer (CRC). First, we found that overexpressions of c-MET/EGFR were associated with the infiltration of tumor immune cells and cancer-associated fibroblasts, and were of prognostic relevance in CRC cohorts. We also observed that genetic alterations of c-MET/EGFR in CRC co-occurred with other gene alterations and were associated with overexpression of messenger (m)RNA of some cancer hallmark proteins. More specifically, DNA-methylation and somatic copy number alterations of c-MET/EGFR were associated with immune infiltration, dysfunctional T-cell phenotypes, and poor prognoses of the cohorts. Moreover, we describe two novel gefitinib-inspired small molecules derivatives of 3-phenyl-2H-benzo[e] [1,3]-oxazine-2,4(3H)-dione, NSC777205 and NSC777207, which exhibited wide-spectrum antiproliferative activities and selective cytotoxic preference for drug-sensitive and multidrug-resistant melanoma, renal, central nervous system, colon, and non-small cell lung cancer cell lines. We further provided in silico mechanistic evidence implicating c-MET/EGFR/phosphatidylinositol 3-kinase (PI3K)-mammalian target of rapamycin (mTOR) inhibition in anticancer activities of those compounds. Our overall structure-activity relationship study revealed that the addition of an –OCH3 group to salicylic core of NSC777207 was not favorable, as the added moiety led to overall less-favorable drug properties as well as weaker anticancer activities compared to the properties and activities demonstrated by NSC777205 that has no –OCH3 substituent group. Further in vitro and in vivo analyses in tumor-bearing mice are ongoing in our lab to support this claim and to unravel the full therapeutic efficacies of NSC777205 and NSC777207 in CRC.

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